1. Technical Field of the Invention
The present invention relates to the formulation of a bradykinin antagonist into topically applicable cosmetic, pharmaceutical or dermatological compositions, for the treatment of sensitive human skin, as well as to therapeutic/cosmetic compositions containing a bradykinin antagonist for reducing or eliminating completely the irritant effects elicited by certain active agents, and especially by certain bioactive agents conventionally employed in the cosmetics, pharmaceutical and/or dermatological arts.
2. Description of the Prior Art
It is known to this art that certain skins are more sensitive than others. The symptoms of sensitive skin were heretofore poorly characterized and the problem of these skins was, as a result, poorly defined; the exact mechanism involved in the sensitivity--nonallergic cutaneous hyperreactivity--of the skin, was unknown. In certain quarters it was believed that a sensitive skin was a skin which reacted to cosmetic products, while others believed that it concerned a skin which reacted to a variety of external factors, not necessarily associated with cosmetic and/or dermatological products.
Certain tests have been conducted in attempting to define sensitive skin, for example tests using lactic acid and DMSO which are known to be irritant substances: see, for example, the article by K. Lammintausta et al, Dermatoses, 36, pages 45-49 (1988); and the article by T. Agner and J. Serup, Clinical and Experimental Dermatology, 14, pages 214-217 (1989). However, these tests did not make it possible to characterize sensitive skin completely.
Moreover, sensitive skin was likened to allergic skin.
Taking account of the ignorance of the characteristics of sensitive skin, it was hitherto very difficult to treat it and it was treated indirectly, for example by limiting, in the cosmetic or dermatological compositions, active species eliciting an irritant effect, such as surfactants, preservatives or perfumes, as well as certain otherwise bioactive agents.
The assignee hereof has now conducted many clinical tests and has been able to determine the symptoms associated with sensitive skin. These symptoms are, in particular, subjective signs, which are essentially "dysaesthesic sensations." By the term "dysaesthesic sensations" are intended more or less painful sensations experienced in an area of skin, such as stinging, tingling, itching or pruritus, burning, inflammation, discomfort, pulling, etc.
The assignee hereof has also been able to demonstrate that a sensitive skin is not an allergic skin. Indeed, an allergic skin is a skin which reacts to an external agent, an allergen, which triggers an allergic reaction. This is an immunological response which occurs only when an allergen is present and which affects only sensitized individuals. To the contrary, the essential characteristic of sensitive skin, according to the assignee hereof, is a mechanism of response to external factors, which may be the case for any individual, even if the individuals said to have sensitive skin react faster thereto than the other individuals. This mechanism is not immunological.
It has now been determined that sensitive skin can be divided into two major clinical forms; irritable skin and intolerant skin.
An irritable skin is a skin which reacts by a pruritus, namely, by itching or by stinging, to various factors such as the environment, emotions, foods, the wind, rubbing, shaving, soap, surfactants, hard water having a high calcium concentration, temperature variations, or wool. In general, these signs are associated with a dry skin with or without dartres, or with a skin which displays an erythema.
An intolerant skin is a skin which reacts, by sensations of inflammation or pulling, but also in the same manner as irritable skin by a pruritus, i.e., by itching or stinging. Intolerant skin is also characterized by tingling and/or redness to various factors such as the environment, emotions and foods. In general, these signs are associated with an erythema and with a skin with or without dartres.
In general, sensitive skin is defined by a specific reactivity of the skin. This hyperreactivity may, in particular, be triggered by environmental, emotional or dietary factors or, alternatively, by the application of or contacting with cosmetic or dermatological products. This hyperreactive state which defines sensitive skin distinguishes such skin from the ubiquitous reactivity initiated by irritant agents, which induce a skin irritation in virtually all individuals.
This hyperreactive state is experienced and recognized by individuals suffering therefrom, as a "sensitive skin."
"Sensitive" scalps have a more unequivocal clinical semeiology: the sensations of pruritus and/or of stinging and/or of inflammation are essentially triggered by local factors such as rubbing, soap, surfactants, hard water having a high calcium concentration, shampoos or lotions. These sensations are also sometimes triggered by factors such as the environment, emotions and/or foods. Erythema and hyperseborrhoea of the scalp and the presence of dandruff are often associated with the above signs.
Moreover, in certain anatomical regions such as the major folds (groin, genital, axillary, popliteal, anal and submammary regions, and in the crook of the elbow) and the feet, sensitive skin is reflected in pruriginous sensations and/or dysaesthesic sensations (inflammation, stinging) associated in particular with sweat, rubbing, wool, surfactants, hard water having a high calcium concentration and/or temperature variations.
The assignee hereof has also developed a test in order to determine whether or not a skin is sensitive. Indeed, after having carried out a multitude of tests for the purpose of defining sensitive skin, it has now surprisingly been found that there is a nexus between individuals with sensitive skin and those who react to a topical application of capsaicin.
The capsaicin test entails applying, to about 4 cm.sup.2 of skin, 0.05 ml of a cream containing 0.075% of capsaicin and in noting the appearance of subjective signs induced by this application, such as stinging, burning and itching. In individuals having sensitive skin, these signs appear between 3 and 20 minutes after application and are succeeded by the appearance of an erythema which begins at the edge of the zone of application.
Hitherto, capsaicin was used as a medicinal active agent, in particular for treating zona pains. Capsaicin induces a release of neuropeptides from sensitive nerve fibers, and in particular of tachykinins and of CGRP (peptide derived from the calcitonin gene: Calcitonin Gene Related Peptide) which originate from epidermal and dermal nerve endings. It has been observed that the physiopathological pattern common to all conditions of sensitive skin was associated with a marked ability to release neuropeptides, and more particularly Substance P and CGRP, into the skin. It is known, moreover, that these neuropeptides released by sensitive epidermal nerve endings induce a cascade of biochemical events whose first steps involve mastocytes. The binding of these neuropeptides, and in particular Substance P, to the mastocyte receptors induces a release of a number of proinflammatory mediators.